ZNF41

protein-coding

zinc finger protein 41, the group of Zinc fingers C2H2-type

Gene summary

This gene encodes a protein that contains KRAB-A and KRAB-B domains multiple zinc finger DNA binding motifs and finger linking regions characteristic of the Kruppel family. An initial study suggested that this gene may be associated with X-linked cognitive disability, but a later study has called this finding into question (PMID:23871722).[provided by RefSeq, Apr 2016]

MANE transcript

NM_001324144.2

Inheritance

ClinVar variants

U:105B:34

Top phenotype

Mental retardation, X-linked 89

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chrX:47,445,178-47,483,222

External References & Databases

Ensembl (ENSG00000147124)

Transcript & Mutation Effects

hg38 • Region Span ~38.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

non-syndromic X-linked intellectual disabilityNO_KNOWN

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: ClinGen

The association between ZNF41 and X-linked non-syndromic intellectual disability was first suggested in 2013 (Shoichet et al., PMID: 14628291). This study reported three unrelated families with intellectual disability and variants involving ZNF41. One female was found to have a de novo balanced X;7 translocation disrupting ZNF41. This translocation was not counted as evidence because the impact of the breakpoints on neighboring genes cannot be ruled out. The second family had two affected brothers with a maternally inherited missense variant in ZNF41. The third family included an affected male proband and an affected sister with borderline ID with a maternally inherited deep intronic variant in ZNF41 that resulted in loss of specific ZNF41 splice variants. The two ZNF41 sequence variants were found to have high population frequencies in gnomAD (v2.1.1) and were not scored as evidence. No additional studies have been reported since then with causative ZNF41 variants in affected individuals. In summary, there is no valid genetic evidence to support an association between ZNF41 and X-linked nonsyndromic intellectual disability, so this gene-disease association is disputed. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 09/02/2020 (SOP Version 7).

non-syndromic X-linked intellectual disabilityLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Mental retardation, X-linked 89XL

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: The evidence of variants as being related to disease causation has been questioned due to subsequent population-based studies

Refs: 14628291; 23871722

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZNF41 variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 97

not providedTotal: 31

ZNF41-related disorderTotal: 7

History of neurodevelopmental disorderTotal: 5

Abnormality of neuronal migrationTotal: 1

SeizureTotal: 1

Global developmental delayTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001324144.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	13 clinvar	2 clinvar	19
missense			92 clinvar	13 clinvar	6 clinvar	111
nonsense			2 clinvar			2
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	0	0	105	26	8	139

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 98 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001324144.2	RefSeq	NP_001311073.1	4	MANE Select
ENST00000684689.1	Ensembl	ENSP00000508254.1	4	MANE Select
NM_001324139.2	RefSeq	NP_001311068.1	2	Standard
NM_001324140.2	RefSeq	NP_001311069.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gene expression (Transcription)
Generic Transcription Pathway
RNA Polymerase II Transcription

Biological Process

regulation of transcription by RNA polymerase II

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
protein binding
metal ion binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377065
Coding exons: 4
Length: 37068
Individuals with no LoFs: 125727
Homozygous LoFs: 4
Heterozygous LoFs: 12
Defined: 125743
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.30	229	292	0.785	0.0000213	5206
Missense (PolyPhen)		69	104.7	0.65902		1946
Synonymous	0.383	100	105	0.952	0.00000812	1361
Loss of Function	2.78	6	19.1	0.313	0.00000128	413

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00030	0.00025	rare
Latino/Admixed American	0.000036	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000072	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.000079	rare
South Asian	0.000052	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in transcriptional regulation.;

Recessive Scores

pRec: 0.129

Intolerance Scores

LoFtool: 0.831
RVIS EVS: 0.73
RVIS percentile EVS: 86.27

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.316

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium